Compounds of Formula I have been disclosed as potent and medically useful inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5). Daugan A C-M, U.S. Pat. No. 5,859,006 to ICOS; Daugan A C-M and Gellibert F, U.S. Pat. No. 6,143,746 to ICOS:
or salts of solvates thereof, in which: R0 represents hydrogen, halogen or C1-6 alkyl; R1 represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloC1-6 alkyl, C3-8cycloalkyl, C3-8cycloalkyl, C1-3alkyl, arylC1-3alkyl, wherein aryl is phenyl or phenyl substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, methylenedioxy, and mixtures thereof, or heteroarylC1-3alkyl, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, and mixtures thereof; R2 represents an optionally substituted mono-cyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an option each of which are incorporated herein in their entirety ally substituted bicyclic ring
attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen; and R3 represents hydrogen or C1-3 alkyl, or R1 or R3 together represents a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring.
Compound 1, chemically described variously as pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-; as (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione; and as (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino [2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;
comprises a particularly important example of this genus.
Compound 1 and pharmaceutical compositions comprising it have utility both alone and, for certain conditions, in combination with additional agents, for the treatment of: erectile dysfunction, stable, unstable and variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, acute respiratory distress syndrome, malignant hypertension, pheochromocytoma, congestive heart failure, acute renal failure, chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular diseases, vascular disorders, thrombocythemia, inflammatory diseases, myocardial infarction, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, peptic ulcer, gut motility disorders, postpercutaneous transluminal coronary or carotid angioplasty, post-bypass surgery graft stenosis, osteoporosis, preterm labor, benign prostatic hypertrophy, and irritable bowel syndrome, in humans and in animals; erectile dysfunction in male humans and animals; and female arousal disorder in females. Daugan A C-M and Gellibert F, U.S. Pat. No. 6,143,746 to ICOS; Daugan A C-M, U.S. Pat. No. 6,140,329 to ICOS; Daugan A C-M, U.S. Pat. No. 5,859,006 to ICOS; Anderson N R and Gullapalli R P, U.S. Pat. No. 6,841,167 to Lilly Icos; Allemeier L L et. al., U.S. Pat. No. 6,613,768 to Lilly Icos.
Definitions and descriptions of these conditions are known to the skilled practitioner and are further delineated, for instance, in the above patents and references contained therein; Harrison's Principles of Internal Medicine 16th Edition, Kasper D L et. al. Eds., 2004, McGraw-Hill Professional; and Robbins & Cotran Pathologic Basis of Disease, Kumar V et. al. Eds., 2004, W. B. Saunders. Compound 1 is currently indicated for the treatment of erectile dysfunction. United States Food and Drug Administration (FDA) New Drug Application (NDA) no. 021368; see label approved on Mar. 31, 2005; http://www.fda.gov/cder/foi/label/2005/021368s004,005lbl.pdf.
The combination of Compound 1 with additional agents extends or enhances its utility in the treatment of sexual deficient states in humans, including those with epilepsy, craniopharyngioma, hypogonadism, or who have had a hysterectomyoophorectomy, hysterectomy or oophorectomy; and to the induction of mating in non-human animals. McCall R B and Meglasson M D, U.S. Pat. No. 6,903,127 to Pharmacia & Upjohn; McCall R B and Meglasson M D, U.S. Pat. No. 6,890,945 to Pharmacia & Upjohn; McCall R B and Meglasson M D, U.S. Pat. No. 6,809,112 to Pharmacia & Upjohn. See also Shapira N, US Patent Application 20040009957; Adams M A et. al. US Patent Application 20040063719, Queen's University at Kingston and Callegy Pharmaceuticals Applicants; Fox DNA and Hughes B, US Patent Applications 20040077624 and 20040132731; Hepworth D, US Patent Application 20040180958, Pfizer Applicant; Kalvinish I et. al. US Patent Application 20040242590; US Patent Applications 20030225060, 20040097546, 20040204398, and 20040266821, Merck Applicant; Thomas T N, US Patent Application 20050009835; Bictash M N et. al., US Patent Application 20050049255, Pfizer Applicant; Chiang P et. al. US Patent Applications 20030125334, 20050020604, 20050032809, and 20050054656, Pfizer Applicant; Santel D J, US Patent Application 20050101608; and Ghofrani A, US Patent Application 20050107394.
Additionally disclosed uses for Compound 1 include methods of treating males with low sperm count to promote fertilization of an ovum; combinations with additional agents to treat hyperglycemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridemia, diabetes, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, obesity, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, syndrome X, coronary heart disease, angina pectoris, vascular restenosis, and endothelial dysfunction; methods of reducing insulin resistance and preventing ischemia/reperfusion injury; combinations with other agents to treat depression, epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, anxiety, panic, pain, irritable bowel syndrome, sleep disorders, osteoarthritis, rheumatoid arthritis, neuropathological disorders, visceral pain, functional bowel disorders, inflammatory bowel diseases, pain associated with dysmenorrhea, pelvic pain, cystitis, pancreatitis, cyclical oedema, Menires disease, hyperaldosteroneism (primary and secondary), hypercalciuria and lower urinary tract symptoms, other than urinary incontinence, associated with overactive bladder and/or benign prostatic hyperplasia; methods for stimulating ovarian follicular growth, for preventing or treating a condition involving fibrosis, and for alleviating pain or spasticity in a patient suffering from spinal cord injury. Quay S C, World Patent Application WO2004069167, Nastech Applicant; Cohen D S, US Patent Application 20030139429; Lautt W W and Macedo P, US Patent Application 20030181461; Kukreja R, US Patent Application 20040009957; Patrick J and Davis M, US Patent Application 20050143314; Nonaka S and Maruyama T, US Patent Application 20040082653; Rawson D J, US Patent Application 20040132801, Warner-Lambert Applicant; Dack K N et. al., US Patent Application 20040138274, Warner-Lambert Applicant; Field M J and Williams R G, US Patent Applications 20040092522 and 20040157847, Warner-Lambert Applicant; Westbrook S L and Zanzinger J F, US Patent Application 20040167095; Taylor C P Jr et. al., US Patent Application 20040180958, Warner-Lambert Applicant; Burgess G M, US Patent Application 20040186046, Pfizer Applicant; Palmer S S et. al. US Patent Application 20040259792; Lautt W W, US Patent Application 20050049293; Gonzalez-Cadavid, N F and Rajfer J, US Patent Application 20050085486; Takasaka S, US Patent Application 20050107405, Warner-Lambert Applicant; and Lautt W W and Macedo P, US Patent Application 20050119272, DiaMedica Applicant.
Compound 1 has been characterized by in vitro inhibition studies of human cyclic guanosine monophosphate-specific phosphodiesterases and has been demonstrated to have high potency and selectivity for the type 5 isoform over other human phosphodiesterases. In cultured rat aortic smooth muscle cells, Compound 1 dose-dependently increases intracellular concentrations of cGMP. For example, see Porst H, Int. J. Impot. Res. 2002 14(Suppl 1): S57; Daugan A et. al. J. Med. Chem. 2003 46: 4533; Daugan A C-M and Gellibert F, U.S. Pat. No. 6,143,746 to ICOS. PDE subtype selectivity is believed to be clinically important due to the potential for side effects associated with inhibition of other PDEs. For instance, inhibition of the PDE6 and possibly PDE1 subtypes are believed to cause the flushing, disrupted color vision and headaches clinically associated with less selective inhibitors (see, for instance, Bischoff E, Int. J. Impot. Res. 2004 16(Suppl. 1): S11; Kuan J and Brock G, Expert Opin. Investig. Drugs 2002 11: 1605).
Compound 1 has also been characterized in the spontaneous rat hypertension model as causing significant and long-lived blood pressure reduction following oral dosing. See e.g. Daugan A et. al., J. Med. Chem. 2003 46: 4533.
In multiple human clinical studies in males with mild to severe erectile dysfunction, treatment with Compound 1 resulted in highly significant patient-reported increases in penetration ability and ability to maintain erection during intercourse versus treatment with placebo. These benefits were observed in a wide cross section of patients including those suffering from spinal cord injuries or diabetes. See, e.g. Giuliano F et. al. Eur. Urol. 2000 37(Suppl. 2): Abst. 320; Bella A J and Brock G B, Curr. Urol. Rep. 2003 4: 472; Del Popolo G et. al. Spinal Cord. 2004 42: 643; Fonseca V et. al., Diabetologia 2004 47: 1914. Studies comparing patient preferences between Compound 1 and another commercial PDE5 inhibitor have consistently indicated a statistically significant preference for Compound 1, which has been suggested to be due to the longer pharmacological half life of Compound 1 providing a greater window of opportunity for sexual spontaneity. See Doggrell S A, Expert Opin. Pharmacother. 2005 6: 75; Stroberg P et. al., Clin. Ther. 2003 25: 2724; Govier F, Clin. Ther. 2003 25: 2709; Porst H, Int. J. Impot. Res. 2002 14(Suppl. 1): S57.
Following oral administration to humans, Compound 1 is well absorbed, followed by extensive oxidative and phase II metabolism with only a minor amount of Compound 1 being excreted unchanged (FDA NDA no. 02368, label approved on Mar. 31, 2005). The major metabolic pathway proceeds by initial oxidative cleavage of the benzodioxol ring to forming a catechol metabolite. Subsequent phase II metabolism ensues, including mainly methylation and glucuronidation; see Scheme I. In vitro measurements indicate that these metabolites do not contribute to the clinical activity of Compound 1. When Compound 1 is dosed concurrently with inhibitors of cytochrome 3A4 (CYP3A4), clinically meaningful increases in the half-life and exposure of Compound 1 measured as area under the plasma-time concentration curve (AUC) occur, leading to lower labeled dosing recommendations in patients taking such medications.

Burgess G M et. al., US Patent Application 20040186046, Pfizer Inc. Applicant (“the '046 application”), discloses PDE5 inhibitors, including Compound 1, and all isotopic variants thereof, as being useful to treat diabetes. The '046 application suggests that substitution of PDE5 inhibitors with isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. The '046 application does not teach which PDE5 inhibitors, nor what portion of any particular PDE5 inhibitor, should be substituted with isotopes in order to produce greater metabolic stability.
It is therefore desirable to create a compound displaying the beneficial activities of Compound 1, but with a reduced rate of metabolism to further extend its pharmacological effective life.